An aldose reductase inhibitor is useful as a preventive agent and/or a remedy for diabetic complications. The diabetic complications appear in various forms, such as neuropathy, retinopathy, nephropathy, cataracts and keratopathy. It has been known that these diseases are triggered by hyperglycemia and caused by abnormal increase of the production of sorbitol in the polyol pathway to abnormally accumulate a large amount of sorbitol in the cells.
The present aldose reductase inhibitor remarkably and effectively inhibits the activity of aldose reductase, which catalyzes the production of sorbitol in the polyol pathway, to prevent the production of sorbitol. As a result, the present aldose reductase inhibitor acts as a useful preventive agent/remedy for diabetic complications.
Dr. Tsuyoshi Tanimoto [Division of Biological Chemistry and Reference Standards, National Institute of Hygienic Sciences] reported that aldose reductase inhibitors are effective for prevention/treatment of diabetic complications [FARUMASHIA, 24, No. 5, p. 459.about.463 (1988)]. This article discloses the chemical structures and IC.sub.50 (concentrations for inhibiting activities by 50%) of representative aldose reductase inhibitors such as Alrestatin, Tolrestat, 4-Isopropyl-BPOC, Sorbinil, M-79175, Alconil, ADN-138, Epalrestat, CT-112 and Statil.
The effective compounds having the formula [I] comprise both known and novel.
For example, the compounds listed in Table 1 are described, as an antiallergic agent.
TABLE 1 __________________________________________________________________________ ##STR5## Publication R.sub.2 R.sub.3 R.sub.4 __________________________________________________________________________ (A) NHCOCOO-alkyl H H (2-position) (B) NHCOCOO-alkyl H, lower alkyl, H, lower alkyl, lower alkoxy or lower alkoxy or halogen halogen (C) NHCOCOO-alkyl H or halogen NHCOCOO-alkyl (3-position) (5-position) (D) NHCOCOOH H H (3-position) __________________________________________________________________________ Note: (A) Japanese Patent Publication for Opposition Purpose (J. P. Kokoku) No. 591704 (B) J. P. Kokoku No. 591705 (C) J. P. Kokoku No. 591707 (D) Japanese Patent Unexamined Published Application (J. P. Kokai) No. 6344570
The compounds listed in Table 2 are discribed in J. Org. Chem., 21, 311 (1956).
TABLE 2 ______________________________________ ##STR6## A R.sub.5 ______________________________________ CH.sub.2 H CH(CH.sub.3) H C(CH.sub.3).sub.2 H C(CH.sub.3).sub.2 C.sub.2 H.sub.5 ______________________________________
The compounds listed in Table 3 are also described in Zh. Org. Khim., 18, 1981 (1982).
TABLE 3 ______________________________________ ##STR7## R.sub.4 ______________________________________ 3-CH.sub.3, 3-Cl, 3-NO.sub.2, 4-CH.sub.3, 4-Cl, 4-Br, 4-NO.sub.2 ______________________________________
However, it has not been known until now that the present compounds have a useful inhibitory activity for aldose reductase.